Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives

ABSTRACT

A series of non-peptidergic antagonists of NPY have been synthesized and are comprised of nitrogen heterocyclic derivatives of 4-phenyl-1,4-dihydropyridines of Formula (I). ##STR1## As antagonists of NPY-induced feeding behavior, these compounds are expected to act as effective anorexiant agents in promoting weight loss and treating eating disorders.

BACKGROUND OF THE INVENTION

The present invention concerns heterocyclic carbon compounds comprising4-phenyl-1,4-dihydropyridines with a nitrogen heterocycle-containingmoiety attached to the 3-position of the 4-phenyl ring. These compoundsact as NPY antagonists.

A substantial body of art has accumulated over the past two decades withrespect to 4-aryl-1,4-dihydropyridine compounds. A large number of thesepossess calcium antagonist properties and find utility in the treatmentof cardiovascular diseases. Several 4-aryl-1,4-dihydropyridines withpiperidine-ring-containing-substituents have been reported.

A series of compounds of formula (1) was claimed to be ##STR2## usefulas vasodilators, antihypertensives and diuretics in U.S. Pat. No.4,707,486.

A series of dihydropyridines, including compounds of formula (2), weredisclosed and claimed to have antitumor promoting ##STR3## activity inEuropean Patent Application 533,504.

European Patent Application 534,520 discloses related compounds havingformula (3) wherein R⁵ is alkyl, phenyl and aralkyl, ##STR4##

A compound of formula (4) has been disclosed in JO 4049-237-A andclaimed to be an inhibitor of Phospholipase A₂. ##STR5##

Of less significance is a series of antihypertensive dihydropyridineanilide derivatives disclosed in U.S. Pat. No. 4,829,076 and containingcompounds of formula (5) ##STR6## in which B is a chemical bond or analkylene group.

These reference compounds are readily distinguished structurally fromthe compounds of the instant invention by virtue of many of the artcompounds having only simple piperidine substituents attached to thedihydropyridine ring itself as well as by the nature of most of thelinking functional groups, e.g. oxyalkylenyl and carboxylate groups. Incontrast, compounds of the instant invention contain ring-fused orspiro-ring nitrogen heterocycles in a moiety attached to the 3-positionof the 4-phenyl ring by means of an anilide or urea connection. Not onlyare the present compounds structurally novel, they also have beendiscovered to possess novel NPY antagonist activity while having greatlyreduced calcium antagonist properties.

In summary, the prior art does not disclose nor suggest the uniquecombination of structural fragments which embody these noveldihydropyridine derivatives having good antagonist activity at NPY Y₁receptor sites and reduced effects on other systems.

Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982from porcine brain.¹,2 The peptide is a member of a larger peptidefamily which also includes peptide YY (PYY), pancreatic peptide (PP),and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y isvery highly conserved in a variety of animal, reptile and fish species.It is found in many central and peripheral sympathetic neurons and isthe most abundant peptide observed in the mammalian brain. In the brain,NPY is found most abundantly in limbic regions. The peptide has beenfound to elicit a number of physiological responses including appetitestimulation, anxiolysis, hypertension, and the regulation of coronarytone.

Structure-activity studies with a variety of peptide analogs (fragments,alanine replacements, point mutations, and internal deletion/cyclizedderivatives) suggest a number of receptor subtypes exist for NPY.^(2b)These currently include the Y₁, Y₂, Y₃, and the Y_(1-like) or Y₄subtypes.

Although specific peptidic antagonists have been identified for most ofthe subtypes, few selective non-peptidic antagonists (see Charts 1 and2) have been reported to date. Several competitive but nonselective,non-peptidic antagonists are known, however (Chart 1). The heterocyclicguanidine derivative He 90481 (4) was found to be a weak but competitiveantagonist of NPY-induced Ca⁺⁺ entry in HEL cells (pA₂ =4.43).³ Thecompound was also found to have α₂ -adrenergic and histaminergicactivity at this dose range. D-Myo-inositol-1,2,6-triphosphate (5) wasreported to be a potent but non-competitive antagonist to NPY-inducedcontractions in guinea pig basilar artery.⁴ Similarly, thebenextramine-like bisguanidines 6a and 6b were reported to displace ³H-NPY in rat brain (IC₅₀, 19 and 18.4 μM) and to display functionalantagonism in rat femoral artery.⁵ The bisguanidine 6b was shown to befunctionally selective for the Y₂ receptor since it antagonized theeffect of the NPY₂ agonist NPY₁₃₋₃₆ but had no effect on thevasoconstrictive activity of the NPY₁ agonist [Leu³¹, Pro³⁴ ]NPY.^(5c)

Compound (6), shown in Chart 2 and known as BIBP 3226⁶, displaces I-125Bolton-Hunter labeled NPY in human neuroblastoma cells (SK-N-MC).Compound (6) antagonized the NPY-induced increase in intracellular Ca⁺⁺in SK-N-Mc cells as well as antagonizing the NPY-induced pressorresponse in pithed rat experiments.

In addition to displacing I-125 labeled NPY and PYY in humanneuroblastoma cells, compound (7), SR 120819A⁷, also antagonizedNPY-related increases in diastolic blood pressure in an anesthetizedguinea pig model.

In sum, the compounds of this invention may be distinguished overcompounds of the prior art on the basis of molecular structure andbiologic activity. There is nothing in the prior art that anticipates orsuggests the novel NPY antagonists of the present invention.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises the compounds of Formula (I), ##STR7##their pharmaceutically acceptable acid addition salts and/or theirhydrates thereof. In the foregoing structural formula, the symbols R¹-R⁵, B and Z have the following meanings.

R¹ is lower alkyl; methyl being preferred.

R² and R³ are independently selected from cyano and lower alkyl, withmethyl being preferred.

R⁴ is selected from --CO₂ R¹, cyano and ##STR8## R⁵ can be hydrogen,halogen, hydroxy, lower alkyl, lower alkoxy, and lower alkenyloxy suchas allyloxy.

B is NH or a chemical bond.

The symbol n is an integer from 2 to 5 with 3 being preferred.

Finally, Z is selected from a group of nitrogen heterocycles consistingof ##STR9##

in which the solid and dotted lines represent either a single or doublecovalent bond.

The term "lower" indicates that the alkyl, alkoxy, or alkenyloxy groupcontains from one to four carbon atoms. Preferred compounds of theinstant invention are Formula (I) compounds wherein R² and R³ aremethyl; R⁴ is --CO₂ Me; R⁵ is hydrogen; and B is NH. Most preferredcompounds further are those wherein Z is ##STR10##

The compounds of the present invention can exist as optical isomers andboth the racemic mixtures of these isomers as well as the individualoptical isomers themselves are within the scope of the presentinvention. The racemic mixtures can be separated into their individualisomers through well known techniques such as the separation of thediastereomeric salts formed with optically active acids, followed byconversion back to the optically active bases.

As indicated, the present invention also pertains to thepharmaceutically acceptable non-toxic salts of these basic compounds.Such salts include those derived from organic and inorganic acids suchas, without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, maleic acid, fumaric acid,sorbic acid, aconitic acid, salicylic acid, phthalic acid, enanthicacid, and the like.

The compounds of the present invention may be produced by the followingprocesses which employ variations of the Hantzsch synthetic reactionapplied to the appropriate starting materials. General processes forpreparing Formula (I) compounds are outlined in Schemes 1 and 2. Thesymbols, such as R¹ -R⁵, B, n and Z are as previously defined, and X ischloro or bromo. The dihydropyridine intermediate (V) can be prepared bythe reaction of 3-nitrobenzaldehyde and the requisite acetoacetates,such as compound (VI) wherein R⁴ is e.g. carbethoxy, under standardHantzsch condensation conditions⁸ (e.g. ammonium acetate in refluxingisopropanol) if symmetrical intermediates of Formula (V) are desired.Symmetrical intermediate (V) compounds would have R² ═R³ and R⁴ ═--CO₂R¹. Unsymmetrical dihydropyridines (V) are obtained using modifiedHantzsch conditions starting with Knoevenagel adducts (VII)⁹ and theappropriate dicarbonyl compounds (VI). A number of thesedihydropyridines (V) have been described in the literature.¹⁰ Reductionof intermediate (V) compounds catalytically or by using either an ironreduction method (Fe/NH₄ Cl/aq. alcohol)¹⁵ or a Ni(OAc)₂ /NaBH₄ exchangeresin procedure¹¹ provides the amino intermediates (IV). A number ofthese aniline derivatives have also been described in the literature.¹²Scheme 1 illustrates their conversion into anilide-linked Formula (I)compound. Reaction of (IV) with a haloacyl halide (VIII) gives compound(III), and subsequent treatment with appropriate heterocyclicintermediate compounds (X) yields the desired Formula (I) products.

Syntheses of Formula (I) compounds containing urea linkages are shown inScheme 2. In process A, the aniline intermediate (IV) is reacted with anappropriate haloalkyl isocyanate (IX) to produce intermediate compound(II) which is then further reacted with a heterocyclic intermediate (X)to yield urea-linked Formula (I) product. Process B involves theconversation of the aniline intermediate (IV) to an isocyanateintermediate (XXXIV) via the carbamate intermediate (XXIV). Reaction ofthe isocyanate compound (XXXIV) with an aminoalkyl-substitutedheterocyclic compound (XX) gives the urea-linked Formula (I) product ingood overall yield. It will be appreciated by one skilled in the artthat (XX) intermediates may be readily obtained by alternative syntheticschemes in addition to the scheme illustrated.

Certain intermediates of Formula (V) require modified syntheses and someof these are exemplified in Scheme 3. Synthesis A shows hydrolysis of anacetal derivative (XIII) following a general synthetic route similar tothat reported by Satoh¹³. Hydrolysis of the acetal (XIII) isaccomplished by acid treatment (HCl/acetone). The resulting aldehyde(XII) is converted to the oxime derivative via reaction withhydroxylamine in acetic acid and then dehydrated by heating in aceticanhydride to produce the cyano-substituted intermediate (V). Conversionof a cyano-substituted nitrobenzene compound (V) to thecyano-substituted aniline intermediate (IV) is accomplished with Fe/NH₄Cl in alcohol.

Synthesis B of Scheme 3 outlines preparation of oxadiazole substitutedintermediates. A dihydropyridine carboxylic acid starting material (XIV)is coupled with acetamidoxime via carbonyldiimidazole (CDI) and thenheated at about 200° to convert the intermediary oxime ester to theoxadiazole nitro compound (V). Reduction of (V) to the oxadiazolesubstituted aniline compound (IV) is carried out using the iron methodin order to preclude N-O bond cleavage seen with hydrogenolysis.

For products wherein R⁵ is other than hydrogen, the reaction sequence(as in Schemes 1 and 2) begins using the appropriate R⁵ -substitutednitrobenzaldehyde except when R⁵ is hydroxy. In this case, (shown inScheme 4) compound (V), wherein R⁵ is hydroxy, is O-allylated bytreatment with NaH/allyl bromide to give an intermediate (V) wherein R⁵is allyloxy. Iron reduction provides the aniline intermediate (IV) whichis reacted sequentially with an appropriate haloalkyl isocyanate orhaloacyl halide followed by a heterocyclic reactant to provide theFormula (I) compound wherein R⁵ is allyloxy. Deprotection is achievedusing PdCl₂ in a HOAc/NaOAc buffer to yield the R⁵ -OH Formula (I)product.

Heterocyclic starting compounds (X) are commercially available and/ordescribed in the chemical literature.²⁰ A convenient synthesis is shownfor a specific heterocyclic intermediate compound in Scheme 5. The cyanointermediate (XXIII) is prepared in two steps from an appropriatestarting tetralone. Treatment of (XXIII) with lithium diisopropylamineand reaction with ethyl acetate provides compound (XXII) which undergoescatalytic hydrogenation to form the cyclized intermediate (XXI).Reduction of (XXI) yields the desired HZ compound as (X). Additionalreaction intermediates and Formula (I) products can be prepared byappropriate modification of the foregoing synthetic schemes andprocedures. Such modifications would be obvious to practitioners skilledin the chemical art. Additional examples and experimental procedures areprovided infra.

The compounds of this invention demonstrate binding affinity at NPY Y₁receptors. This pharmacologic activity is assayed in SK-N-MC (humanneuroblastoma) cell membranes using iodine-125-labeled I-PYY as aradioligand. The compounds of this invention had good binding affinitiesas evidenced by IC₅₀ values being about 10 μM or less at NPY Y₁receptors. Preferred compounds have IC₅₀ values less than 100 nM andmost preferred compounds have IC₅₀ values of less than 10 nM. Althoughas a class, these types of dihydropyridines have significant affinityfor α₁ -adrenergic receptors and/or Ca⁺⁺ channels, the compounds of thisinvention possess much weaker affinities for adrenergic receptors andCa⁺⁺ channels. As such, these compounds act as selective NPY antagonistsat NPY Y₁ receptor sites. There is evidence that NPY contributes tocertain symptoms in these disorders: hypertension, eating disorders, anddepression/anxiety;¹⁸ as well as circadian rhythms. Compounds of thisinvention are expected to be useful in treating these disorders.

Selected compounds are tested further for their ability to blockNPY-induced feeding in test animals by intraperitoneal administration tothe animal prior to inducing feeding behavior with NPY. Taken together,these tests indicate that the compounds of this invention would beuseful anorexiants and would function as anti-obesity agents withfurther use in various clinical eating disorders. Thus, another aspectof the invention concerns a process for reducing food intake in an obesemammal or a mammal with an eating disorder. The process comprisessystemic administration to such a mammal of an anorexiant-effective doseof a Formula (I) compound or a pharmaceutically acceptable acid additionsalt and/or hydrate thereof.

On the basis of pharmacologic testing, an effective dose givenparenterally could be expected to be in a range of about 0.05 to 1 mg/kgbody weight and if given orally would be expected to be in the range ofabout 1 to 20 mg/kg body weight.

For clinical applications, however, the dosage and dosage regimen mustin each case be carefully adjusted, utilizing sound professionaljudgment and considering the age, weight and condition of the recipient,the route of administration and the nature and gravity of the illness.Generally, the compounds of the instant invention will be administeredin the same manner as for available anorexiant drugs such asDiethylpropion, Mazindol, or Phentermine and the daily oral dose wouldcomprise from about 70 to about 1400 mg, preferably 500 to 1000 mgadministered from 1 to 3 times a day. In some instances, a sufficienttherapeutic effect can be obtained at lower doses while in others,larger doses will be required.

The term systemic administration as used herein refers to oral, rectal,and parenteral (i.e. intramuscular, intravenous, and subcutaneous)routes. Generally, it will be found that when a compound of the presentinvention is administered orally, which is the preferred route, a largerquantity of reactive agent is required to produce the same effect as asmaller quantity given parenterally. In accordance with good clinicalpractice, it is preferred to administer the instant compounds at aconcentration level that will produce effective anoretic effects withoutcausing any harmful or untoward side effects. Similarly, the instantcompounds can be administered to treat hypertension, depression andanxiety disorders.

Therapeutically, the instant compounds are generally given aspharmaceutical compositions comprised of an effective anorectic amountof a compound of Formula (I) or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier.Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5% of at least one compound ofthe present invention in combination with the pharmaceutical carrier,the carrier comprising one or more solid, semi-solid, or liquid diluent,filler, and formulation adjuvant which is non-toxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit forms; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain 1, 2, 3, 4,or more single doses, or, alternatively, one-half, one-third, orone-fourth of a single dose. A single dose preferably contains an amountsufficient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to thepre-determined dosage regimen usually a whole, half, third, or quarterof the daily dosage administered once, twice, three, or four times aday. Other therapeutic agents can also be present. Pharmaceuticalcompositions which provide from about 50 to 1000 mg of the activeingredient per unit dose are preferred and are conventionally preparedas tablets, lozenges, capsules, powders, aqueous or oily suspensions,syrups, elixirs, and aqueous solutions. Preferred oral compositions arein the form of tablets or capsules and may contain conventionalexcipients such as binding agents (e.g. syrup, acacia, gelatin,sorbitol, tragecanth, or polyvinylpyrrolidone), fillers (e.g. lactose,sugar, maize-starch, calcium phosphate, sorbitol, or glycine),lubricants (e.g. magnesium stearate, talc, polyethylene glycol orsilica), disintegrants (e.g. starch) and wetting agents (e.g. sodiumlauryl sulfate). Solutions or suspensions of a Formula (I) compound withconventional pharmaceutical vehicles are employed for parenteralcompositions such as an aqueous solution for intravenous injection or anoily suspension for intramuscular injection. Such compositions havingthe desired clarity, stability and adaptability for parenteral use areobtained by dissolving from 0.1% to 10% by weight of the active compoundin water or a vehicle consiting of a polyhydric aliphatic alcohol suchas glycerine, propyleneglycol, and polyethelene glycols or mixturesthereof. The polyethyleneglycols consist of a mixture of non-volatile,usually liquid, polyethyleneglycols which are soluble in both water andorganic liquids and which have molecular weights from about 200 to 1500.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The compounds which constitute this invention and their methods ofpreparation will appear more fully from a consideration of the followingexamples which are given for the purpose of illustration only and arenot to be construed as limiting the invention in sphere or scope. Alltemperatures are understood to be in degrees C when not specified.

The nuclear magnetic resonance (NMR) spectral characteristics refer tochemical shifts (δ) expressed in pans per million (ppm) versustetramethylsilane (TMS) as reference standard. The relative areareported for the various shifts in the proton NMR spectral datacorresponds to the number of hydrogen atoms of a particular functionaltype in the molecule. The nature of the shifts as to multiplicity isreported as broad singlet (br s), singlet (s), multiplet (m), doublet(d), triplet (t) doublet of doublets (dd), quartet (q) or pentuplet (p).Abbreviations employed are DMSO-d₆, (deuterodimethylsulfoxide), CDCl₃(deuterochloroform), and are otherwise conventional. The infrared (IR)spectral descriptions include only absorption wave numbers (cm⁻¹) havingfunctional group identification value. The IR determinations wereemployed using potassium bromide (KBr) as diluent. The elementalanalyses are reported as percent by weight.

A. Preparation of Intermediates

1. Formula (VII) Compounds

Example 1: General Procedure for the Preparation of Knoevenagel Adducts(VII)

Following a general method reported by Jones⁹, a mixture of 300 mmoleach of 3-nitrobenzaldehyde and the requisite β-keto ester was dissolvedin 250 mL of toluene and piperidine (2.5 mL) and glacial HOAc (5 mL)were added. The solution was then allowed to reflux several hr duringwhich time the theoretical amount of H₂ O was removed by a Dean-Starktrap. The toluene was then removed in vacuo and the resultingKnoevenagel products purified by flash chromatography (SiO₂ :EtOAc/Hex)or crystallization.

Example 2: 3-(3-Nitrophenyl)-2-(1-oxobutyl)-2-propenoic acid, ethylester

The yellow oil was isolated as a mixture of E and Z isomers in 47%yield: ¹ H NMR (CDCl₃)δ 8.23 (m, 2H), 7.52 (m, 3H), 4.32 (m, 2H), 2.67and 2.53 (t, 2H, J=7.2 Hz), 1.66 (m, 2H), 1.29 (m, 3H), and 0.97 and0.87 (t, 3H, J=7.4 Hz). Anal. Calcd for C₁₅ H₁₇ NO₅ : C, 61.85; H, 5.88;N, 4.81. Found: C, 61.76; H, 5.86; N, 4.82.

Example 3: 2-(Dimethoxyacety)-3-(3-nitrophenyl-2-propenoic acid, ethylester

This adduct was isolated as an orange oil in 34% yield: ¹ H NMR (CDCl₃)δ8.34-8.23 (m, 2H), 7.99-7.70 (m, 3H), 4.94-4.93 (m, 1H), 4.30-4.22 (m,2H), 3.79 (d, 1H, J=8 Hz), 3.35-3.33 (m, 6H), 1.28-1.13 (m, 3H). Anal.Calcd. for C₁₅ H₁₇ NO₇ : C, 55.73; H, 5.30; N, 4.33. Found: C, 55.28; H,4.84; N, 4.59.

2. Formula (V), (XII), and (XIII) Intermediates

Example 4: General Method for the Preparation of DihydropyridineIntermediates (V)

For the symmetrical dihydropyridines of Formula (V), the requisiteβ-keto ester (126 mmol), 3-nitrobenzaldehyde (63 mmol), and NH₄ OAc (95mmol) were refluxed for several h in 150 mL of EtOH using standardHantzsch conditions⁸. The crude reaction mixture was cooled to ambienttemperature and the volatiles removed in vacuo. The symmetricaldihydropyridines were crystallized from EtOH. Generally, for theasymmetrical Formula (V) intermediate, a mixture of the requisiteKnoevenagel adduct (VII) (70 mmol) and methyl 3-aminocrotonate (70 mmol)was refluxed in i-PrOH overnight (24 h). The volatiles were then removedin vacuo and the crude products recrystallized from EtOH.

Example 5:1,4-Dihydro-2-methyl-4-(3-nitrophenyl)-6-propyl-3,5-pyridinedicarboxylicacid, ethyl⁵ methy³ ester

The compound was obtained as a bright yellow solid in 34% yield; mp102°-105° C.; ¹ H NMR (CDCl₃)δ 8.09 (t, 1H, J=2 Hz), 7.99-7.96 (m, 1H),7.63-7.59 (m, 1H), 7.35 (t, 1H, J=8 Hz), 5.77 (br s, 1H), 4.14-3.99 (m,2H), 3.63 (s, 3H), 2.77-2.61 (m, 2H), 2.34 (s, 3H), 1.72-1.53 (m, 2H),1.20 (t, 3H, J=7 Hz), 0.97 (t, 3H, J=7.4 Hz). Anal. Calcd. for C₂₀ H₂₄N₂ O₆ •0.2H₂ O: C, 61.43; H, 6.03; N, 7.16. Found: C, 61.57; H, 6.14; N,7.09.

Example 6:1,4-Dihydro-2-methyl-6-(dimethoxymethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid, ethyl⁵ methyl³ ester (XIII)

The compound was obtained in 35% yield after purification by flashchromatography (SiO₂ : EtOAc/Hex): mp 118°-122° C.; ¹ H NMR (CDCl₃)δ8.14 (t, 1H, J=2 Hz), 8.02-7.99 (m, 1H), 7.65-7.61 (m, 1H), 7.38 (t, 1H,J=8 Hz), 6.82 (br s, 1H), 6.03 (s, 1H), 5.13 (s, 1H), 4.17-4.06 (m, 2H),3.64 (s, 3H), 3.48 (s, 3H), 3.43 (s, 3H), 2.38 (s, 3H), 1.24 (t, 3H, J=7Hz); ¹³ C NMR (CDCl₃)δ 167.4, 166.0, 149.3, 148.3, 145.1, 143.9, 134.2,128.8, 122.9, 121.5, 104.7, 102.5, 98.5, 60.4, 55.7, 55.1, 51.2, 40.0,19.7, 14.1. Anal. Calcd. for C₂₀ H₂₄ N₂ O₈ : C, 57.14; H, 5.75; N, 6.66.Found: C, 57.07; H, 5.64; N, 6.64.

Example 7:1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid, n-butyl methyl ester

A solution of n-butyl acetoacetate (0.10 mole), methyl 3-aminocrotonate(0.10 mole), 3-nitrobenzaldehyde (0.10 mole) and 150 mL of i-PrOH wasrefluxed overnight (18 h). The volatiles were removed in vacuo and theresidue purified by flash chromatography (SiO₂ : EtOAc/Hex) to furnishthe product in 49% yield as low melting, yellow solid: mp 69°-70° C.Anal. Calcd for C₂₀ H₂₄ N₂ O₆ : C, 61.85; H, 6.23; N, 7.21. Found: C,62.02; H, 6.21; N, 6.95.

Example 8:2-Cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid, ethyl³ methyl⁵ ester

The acetal intermediate of Example 6 (XIII) (24 mmol) was taken up in 80mL of acetone and 6N HCl (8 mL ) was added. After stirring at ambienttemperature for 1.5 h, the solvent was removed in vacuo. The resultingsolid was rinsed with one portion of H₂ O and then filtered.Purification by flash chromatography (SiO₂ : EtOAc/Hex) furnished theformyl derivative (XII) in 88% yield as an orange solid: mp 111°-114°C.; ¹ H NMR (CDCl₃)δ 8.12-8.01 (m, 2H), 7.61-7.46 (m, 1H), 7.41 (t, 1H,J=8 Hz), 7.04 (br s, 1H), 5.23-5.22 (m, 1H), 4.30-4.14 (m, 2H), 3.77 (s,1H), 3.64 (s, 3H), 2.43 (s, 3H), 1.28 (t, 3H, J=7 Hz); ¹³ C NMR (CDCl₃)δ186.5, 167.0, 165.2, 148.4, 147.6, 145.2, 139.0, 134.2, 129.3, 123.0,122.1, 115.0, 101.9, 61.6, 52.4, 40.7, 19.6, 14.1. Anal. Calcd. for C₁₈H₁₈ N₂ O₇ : C, 57.75; H, 4.85; N, 7.48. Found: C, 57.61; H, 4.60; N,7.33.

The formyl intermediate ((XII); 8.7 mmol) was dissolved in 25 mL glacialacetic acid and NH₂ OH•HCl (9.6 mmol) and NaOAc (12 mmol) were added.The solution was stirred at room temperature for 2.5 h and then Ac₂ O(29 mmol) was added and the reaction stirred for an 1.5 h at roomtemperature and at 94° C. for an additional 4 h. The excess HOAc and Ac₂O were removed in vacuo. Water was added to the residue and the aq layerwas neutralized with aq NaHCO₃. The suspension was extracted with EtOAcand the combined organic fractions were washed once with H₂ O, and thendried over MgSO₄. After filtration, the flitrate was concentrated invacuo to give an oil which solidified on standing. The cyano derivative(V) was obtained in 40% yield as a yellow solid after trituration fromEtOAc/Hex: mp 169°-170° C.; ¹ H NMR (CDCl₃)δ 8.14-8.01 (m, 2H),7.63-7.60 (m, 1H), 7.47-7.38 (m, 1H), 7.13 (s, 1H), 5.19 (s, 1H),4.27-4.09 (m, 2H), 3.65 (s, 3H), 2.41 (s, 3H), 1.29 (t, 3H, J=7 Hz); ¹³C NMR (CDCl₃)δ 166.7, 163.7, 148.7, 146.7, 145.5, 134.3, 129.4, 123.0,122.4, 116.5, 113.1, 111.8, 102.1,62.0, 52.0, 39.5, 19.2, 13.9. HRMSCalcd for C₁₈ H₁₈ N₃ O₆ (M+H): 372.1196. Found: 372.1207.

Example 9:1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylicacid, methyl ester

The starting1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid, mono-methyl ester (XIV)¹⁴ (11.1 mmol) was treated with carbonyldiimidazole (12 mmol) in 60 mL of MeCN. After stirring for 2 h,acetamidoxime•HCl (15.8 mmol), and Et₃ N (22.2 mmol) were added. Theresulting mixture was refluxed for 17 h under N₂ and the volatiles werethen removed in vacuo. The residue was taken up in CH₂ Cl₂ and washedwith H₂ O and brine, and dried over MgSO₄. After filtration, thevolatiles were removed in vacuo to give a yellow foam. The crudeintermediate O-acyl amidoxime was purified by flash chromatography (SiO₂: MeOH/EtOAc) to give 3.13 g (73%) of this intermediate. This materialwas then heated neat in a 200° C. oil bath for 20 min under a N₂ flow.The resulting dark residue was recrystallized from EtOAc/Hex to give theoxadiazole intermediate (V) in 37% yield as a yellow crystalline solid:mp 221°-222° C.; ¹ H NMR (DMSO-d₆)δ 9.37 (s, 3H), 7.99 (m, 2H), 7.66 (m,1H), 7.54 (t, 1H, J=7.9 Hz), 5.18 (s, 1H), 3.57 (s, 3H), 2.41 (s, 3H),2.31 (s, 3H), and 2.23 (s, 3H), ¹³ C NMR (DMSO-d₆) δ 175.5, 166.9,166.5, 149.0, 148.0, 146.6, 144.4, 134.1, 130.0, 121.7, 100.7, 95.6,51.1, 39.4, 18.5, 18.3, and 11.4. Anal. Calcd for C₁₈ H₁₈ N₄ O₅ : C,58.37 H, 4.90; N, 15.13. Found: C, 58.56; H, 4.88; N, 14.88.

3. Aniline and Anilide Intermediates of Formulas (IV) and (III)

Example 10: General Reductive Procedures for the Conversion of theNitroaryl Dihydropyridines (V) to the Anilines (IV)

Catalytic Hydrogenation Method A. To a N₂ solution of the nitro aromaticdihydropyridine (V) (10 mmol) in 80 mL of EtOH, was added 0.5-1.0 g of5% Pt on sulfided carbon and the resulting suspension shaken on a ParrHydrogenation apparatus at room temperature under 60 psi of H₂. Afterseveral h the reduction was usually complete as judged by theoretical H₂consumption. The suspension was then filtered through Celite and thefiltrate concentrated in vacuo to give the anilines (IV). These werethen purified by recrystallization or flash chromatography in theindicated solvents. In some of the examples the crude anilinederivatives were converted to a salt form and then recrystallized.

Iron Method B.¹⁵ In a 250-mL three-necked flask equipped with mechanicalstirrer and reflux condenser was added a solution of NH₄ Cl (64 mmol) in50 mL of H₂ O, iron powder (38 mg-atom, 325 mesh) and a solution of thenitro aromatic dihydropyridine (V) (11 mmol) in 50 mL of MeOH. Theresulting mixture was stirred at reflux for 6 h and then filteredthrough Celite and rinsed with copious amounts of MeOH. The filtrate waspartially concentrated in vacuo to yield an aq suspension, which wasextracted with CH₂ Cl₂. The combined organic extracts were dried overNa₂ SO₄, filtered, and the volatiles removed in vacuo to yield the crudeanilines (IV). These were purified as above in the hydrogenation method.

Nickel/Borohydride Resin Method C. According to the general method ofYoon¹¹ the borohydride exchange resin (12 g) was suspended in 40 mL ofMeOH and Ni(OAc)₂ •4H₂ O (0.60 mmol) was added. After stirring severalmin, the requisite nitro aromatic derivative (V) (6 mmol) was added andthe resulting black mixture stirred overnight at room temperature. Afterfiltration through a plug of Celite, the reaction solution wasconcentrated in vacuo to give the reduced aniline derivatives (IV).

Example 11:4-(3-Aminophenyl)-1,4-dihydro-2-methyl-6-propyl-3,5-pyridine-dicarboxylicacid, ethyl⁵ methyl³ ester, fumaric acid salt

This compound was obtained as an orange-brown solid in 91% yield (MethodB): mp 92°-95° C.; ¹ H NMR (MeOD)δ 7.30-7.17 (m, 3H), 7.02-6.99 (m, 1H),6.26 (s, 2H), 4.90 (s, 1H), 4.06 (q, 2H, J=14 Hz), 3.61 (s, 3H),2.78-2.52 (m, 2H), 2.30 (s, 3H), 1.69-1.55 (m, 2H), 1.21 (t, 3H, J=7Hz), 0.97 (t, 3H, J=7.4 Hz); ¹³ C NMR (MeOD)δ 170.5, 169.9, 169.04,151.9, 147.0, 135.0, 134.9, 130.5, 127.5, 122.0, 120.3, 103.2, 103.0,60.9, 51.4, 40.8, 34.7, 23.4, 18.6, 14.7, 14.3. Anal. Calcd. for C₂₀ H₂₆N₂ O₄ •1.0C₄ H₄ O₄ •1.0H₂ O: C, 58.53; H, 6.55; N, 5.69. Found: C,58.86; H, 6.22; N, 5.68.

Example 12:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, ethyl methyl ester (Cf: reference 12a)

This compound was obtained in 92% yield as a grey solid aftercrystallization from EtOAc/Hex (Method A): mp 173°-175° C.

Example 13:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethy-3,5-pyridine-dicarboxylicacid, diethyl ester hydrochloride salt (Cf: reference 12a)

The compound was isolated in 82% yield (Method A) after purification byflash chromatography (SiO₂ : EtOAc/Hex). A small portion of the anilinewas converted to the HCl salt by treatment with ethereal HCl. Aftertrituration from Et₂ O, the compound was obtained as a pale yellowsolid: mp 212°-213° C.

Example 14:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylicacid, dimethyl ester (Cf: reference 12a)

The compound was obtained in 58% yield as a colorless solid aftercrystallization from EtOH (Method A): mp 214°-215° C.

Example 15:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylicacid, n-butyl methyl ester hydrochloride salt

The compound was isolated as a yellow oil in 68% yield (Method A) afterflash chromatography (SiO₂ : EtOAc/Hex). A small portion of the oil wasconverted to the HCl salt by treatment with ethereal HCl: Mp 135°-145°C.; ¹ H NMR (DMSO-d₆)δ 10.20 (br s, 2H), 9.12 (s, 1H), 7.29 (t, 1H,J=7.8 Hz), 7.12 (m, 3H), 4.89 (s, 1H), 3.94 (m, 2H), 3.54 (s, 3H), 2.27(s, 3H), 2.26 (s, 3H), 1.49 (m, 2H), 1.22 (m, 2H), and 0.89 (t, 3H,J=8.0 Hz); ¹³ C NMR (DMSO-d₆)δ 167.2, 166.8, 149.7, 146.1, 132.1, 129.1,125.4, 121.7, 120.6, 101.1, 101.0, 62.9, 50.7, 38.6, 30.3, 18.7, 18.3,and 15.6.

Example 16:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylicacid, 1,1-dimethylethyl methyl ester

The aniline was obtained in 87% yield as a yellow solid afterpurification by flash chromatography (SiO₂ : EtOAc/Hex): mp 85°-90° C.;¹ H NMR (CDCl₃)δ 6.97 (t, 1H, J=7.7 Hz), 6.66 (d, 1H, J=7.7 Hz), 6.58(s, 1H), 6.44 (d, 1H, J=7.8 Hz), 5.53 (br s, 1H), 4.86 (s, 1H), 3.62 (s,3H), 3.50 (br s, 1H), 2.29 (s, 3H), 2.26 (s, 3H), and 1.39 (s, 9H); ¹³ CNMR (CDCl₃)δ 168.2, 167.1, 148.7, 145.9, 144.1, 142.5, 128.6, 118.5,114.9, 113.1, 103.4, 79.8, 50.9, 39.6, 28.3, 19.7, and 19.6. Anal. Calcdfor C₂₀ H₂₆ N₂ O₄ : C, 67.02; H, 7.32; N, 7.82. Found: C, 66.97; H,7.43; N, 7.68.

Example 17:4-(3-Aminophenyl)-1,4-dihydro-2-cyano-6-methyl-3,5-pyridinedicarboxylicacid, ethyl³ methyl⁵ ester

This material was prepared using the general Fe/NH₄ Cl proceduredescribed above for anilines (Method B). Aniline (IV) was obtained in69% yield as a yellow solid: mp 181°-182° C.; ¹ H NMR (CDCl₃)δ 8.73 (s,1H), 6.96 (t, 1H, J=8 Hz), 6.60-6.44 (m, 3H), 4.92 (s, 1H), 4.25-4.08(m, 2H), 3.70 (s, 1H), 3.58 (s, 3H), 2.30 (s, 3H), 1.23 (t, 3H, J=7 Hz);¹³ C NMR (CDCl₃)δ 167.5, 164.5, 146.4, 145.6, 129.2, 118.3, 118.1,117.7, 116.6, 114.7, 114.5, 114.0, 113.8, 101.8, 61.3, 51.2, 39.1, 18.7,14.0. Anal. Calcd. for C₁₈ H₁₉ N₃ O₄ : C, 61.94; H, 5.47; N, 11.53.Found: C, 61.51; H, 5.34; N, 11.75.

Example 18:4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylicacid, methyl ester

This compound was prepared using the iron procedure (Method B). Theaniline derivative was obtained in quantitative yield as a yellow solid:mp 248°-249° C.; ¹ H NMR (DMSO-d₆)δ 9.08 (s, 1H), 6.80 (t, 1H, J=7.7Hz), 6.39 (s, 1H), 6.34 (d, 1H, J=7.7 Hz), 6.27 (d, 1H, J=7.7 Hz), 4.93(s, 1H), 4.88 (br s, 2H), 3.58 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), and2.23 (s, 3H); ¹³ C NMR (DMSO-d₆)δ 175.9, 167.2, 166.2, 148.4, 147.4,144.9, 143.3, 128.5, 114.7, 112.7, 112.0, 101.5, 96.0, 50.7, 39.0, 18.2,and 11.2. HRMS. Calcd for C₁₈ H₂₁ N₄ O₃ (M+H): 341.1614. Found:341.1606.

Example 19:4-(3-Aminophenyl)-5-cyano-1,4-dihydro-2,6-dimethyl-3-pyridinecarboxylicacid, methyl ester

This compound was prepared using the iron procedure (Method B). Theaniline was obtained in 10% yield as a tan solid after recrystallizationfrom EtOH: mp 234°-235° C.; ¹ H NMR (DMSO-d₆)δ 9.09 (br s, 1H), 6.90 (t,1H, J=7.5 Hz), 6.36 (m, 2H), 6.30 (d, 1H, J=7.5 Hz), 5.01 (br s, 2H),4.27 (s, 1H), 3.48 (s, 3H), 2.24 (s, 3H), and 1.99 (s, 3H); ¹³ C NMR(DMSO-d₆)δ 167.2, 148.7, 146.8, 146.0, 145.2, 128.9, 120.2, 114.6,112.5, 99.7, 84.5, 50.7, 40.6, 18.4, and 17.5. Anal. Calcd for C₁₆ H₁₇N₃ O₂ •0.22H₂ O: C, 66.91; H, 6.12; N, 14.63. Found: C, 66.91; H, 6.07;N, 14.40.

Example 20:4-(3-Amino-4-chlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, ethyl methyl ester

This dihydropyridine was obtained using the iron reduction procedure(Method B). It was isolated in 99% yield as light yellow solid: mp68°-90° C.; ¹ H NMR (CDCl₃)δ 7.03 (d, 1H), 6.62 (m, 2H), 5.68 (br s,1H), 4.88 (s, 1H), 4.08 (m, 2H), 3.89 (br s, 2H), 3.63 (s, 3H), 2.29 (s,6H), and 1.21 (t, 3H). Anal. Calcd. for C₁₈ H₂₁ N₂ O₄ Cl: C, 59.26; H,5.80; N, 7.68. Found: C, 59.04; H, 5.79; N, 7.56.

Example 21:4-[3-Amino-4-(2-propenyloxyphenyl)]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid dimethyl ester

To a suspension of hexane-washed Nail (17 mmol, 60% in mineral oil) in 5mL of DMF was added a solution of compound (V), R⁵ ═OH (14.1 mmol) in 50mL of DMF. The resulting dark red solution was stirred at roomtemperature for 10 min and then allyl bromide (22 mmol) was introduced.After the reaction was stirred an additional 21 h, it was poured into300 mL of H₂ O and extracted with CH₂ Cl₂. The combined organic portionswere washed with H₂ O and brine and then dried over MgSO₄. Filtrationand removal of the volatiles in vacuo afforded compound (V), R=allyloxyas an oil which was used without further purification and wassubsequently subjected to the iron reduction method (Method B). Theresulting aniline compound (IV), R-allyloxy was obtained in 50% yieldafter purification by flash chromatography (SiO₂ : EtOAc/Hex) and wasisolated as a pale yellow solid: 155°-157° C.; ¹ H NMR (DMSO-d₆)δ 8.74(br s, 1H), 6.58 (d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=2.1 Hz), 6.26 (d ofd, 1H, J's=8.3 and 2.1 Hz), 6.01 (m, 1H), 5.40 (d, 1H), 5.19 (d, 1H),4.74 (s, 1H). 4.55 (br s, 2H), 4.32 (m, 2H), 3.54 (s, 6H), and 2.22 (s,6H); ¹³ C NMR (DMSO-d₆)δ 167.7, 145.0, 143.7, 140.6, 137.2, 134.4,116.7, 114.7, 113.2, 111.7, 101.8, 68.5, 50.6, 37.6, and 18.2. AnalCalcd for C₂₀ H₂₄ N₂ O₅ : C, 64.50; H, 6.50; N, 7.52. Found: C, 64.32;H, 6.59; N, 7.35.

Example 22: General Procedure for Preparation of Formula (III) AnilideIntermediates

To a solution of an appropriate Formula (IV) aniline intermediate (2.5mmole) in THF (50 mL) at 0° is added a chloroacyl chloride (2.5 mmole)also in THF (15 mL). The reaction is stirred at 0° for 0.5 to 1 hour andthen at room temperature for 0.5 to 1 hour until judged complete.Volatiles are removed in vacuo and the residue is purified, generally byflash silica gel chromatography.

Example 23:1,4-Dihydro-4-[3-[[3-chloro-1-oxo-1-propyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester

4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester (0.8 g, 2.53 mmol) was dissolved in THF (50 mL) andcooled to 0° C. 3-Chloropropionyl chloride (0.32 g, 2.53 mmol) wasdissolved in THF (15 mL) and added dropwise to the mixture over 10 min.The mixture was stirred at 0° C. for 1 h., concentrated in vacuo, andthe residue extracted with CH₂ Cl₂ /brine. The CH₂ Cl₂ layer was driedover Na₂ SO₄, filtered, and concentrated in vacuo. Silica gelchromatography (1:1 to 1:0 EtOAc:hexane gradient) gave the titlecompound (1.05 g, 100%) as a pale yellow foam.

Example 24:1,4-Dihydro-4-[3-[[4-chloro-1-oxo-1-butyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester

4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester (1.0 g, 3.16 mmol) was dissolved in THF (50 mL) andcooled to 0° C. 4-Chlorobutyryl chloride (0.446 g, 3.16 mmol) wasdissolved in THF (10 mL) and added dropwise to the mixture over 5 min.The mixture was stirred at 0° C. for 0.5 h. and then at 23° C. for 1 h.The solvent was removed in vacuo and the concentrate chromatographedover silica gel (1:4 to 1:0 EtOAc:hexane gradient) to give the titlecompound (1.33 g, 100%) as a pale yellow foam.

Example 25:1,4-Dihydro-4-[3-[[5-chloro-1-oxo-1-pentyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester

4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester (2.3 g, 7.28 mmol) was dissolved in THF (50 mL) andcooled to 0° C. 5-Chlorovaleryl chloride (1.13 g, 7.28 mmol) wasdissolved in THF (15 mL) and added dropwise to the mixture over 15 min.The mixture was stirred at 0° C. for 1 h., the solvent removed in vacuo,and the residue was extracted using CH₂ Cl₂ /water. The CH₂ Cl₂ layerwas dried over Na₂ SO₄, filtered, and concentrated in vacuo. Silica gelchromatography (1:1 to 1:0 EtOAc:hexane gradient) of the concentrategave the title compound (3.16 g, 100%) as a pale yellow foam.

4. Intermediates of Formula (II)

Example 26: General Chloroalkyl Isocyanate Procedure for Preparation ofFormula (II) Urea Intermediates

To a solution of the appropriate Formula (IV) aniline intermediate (6mmol) in CH₂ Cl₂ (30 mL) under N₂ is added the chloroalkyl isocyanate (7mmol). The reaction is stirred at room temperature or at reflux untiljudged complete by TLC analysis (2-24 hr). The reaction solution iswashed with H₂ O and brine and then dried (MgSO₄). After filtration, thevolatiles are removed in vacuo and the residue is generally taken up inMeCN (35 mL) and immediately carried on with reaction with a selectedheterocyclic reactant of Formula (X).

Example 27: Preparation of Formula (XXXIV) Isocyanate Intermediates

a)1,4-Dihydro-4-[3-[(methoxycarbonyl)amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester (XXIV). A solution of1,4-dihydro-4-(3-aminophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester,^(10b) (IV: 63.2 g, 200 mmol) and pyridine (18 mL,220 mmol) in CH₂ Cl₂ :MeCN 1:1 (1.5 L) was cooled to 0° C. A solution ofmethyl chloroformate (16 mL, 210 mmol) in CH₂ Cl₂ (50 mL) was addeddropwise over 10 min. Stirring was continued at 0° C. for 30 min, thenthe reaction was warmed to room temperature and stirred for anadditional hour. The reaction mixture was washed with saturated Na₂ CO₃(500 mL) and rinsed with H₂ O (2×500 mL). The organic extract wasfiltered to afford a white solid (37.1 g). The filtrate was then dried(Na₂ SO₄), and the solvent was removed in vacuo. The residue wassuspended in a minimum of EtOAc and filtered. The resulting solid wasrinsed with a small amount of EtOAc, followed by Et₂ O to give anadditional 30.8 g. Both crops were combined for a yield of 67.9 g (91%):mp 215°-218° C.; ¹ H NMR (DMSO-d₆)δ 9.51 (s, 1H), 8.88 (s, 1H), 7.28 (s,1H), 7.22 (d, 1H, J=8.1 Hz), 7.08 (t, 1H, J=7.8 Hz), 6.74 (d, 1H, J=7.8Hz), 4.85 (s, 1H), 3.62 (s, 3H), 3.54 (s, 6H), 2.24 (s, 6H); ¹³ C NMR(DMSO-d₆)δ 167.4, 153.9, 148.2, 145.8, 138.9, 128.3, 121.0, 117.1,115.9, 101.3, 51.5, 50.6, 38.4, 18.2; Anal Calcd for C₁₉ H₂₂ N₂ O₆ •0.1H₂ O: C, 60.66; H, 5.95; N, 7.45. Found: C, 60.50; H, 5.85; N, 7.55.

b)1,4-Dihydro-4-(3-isocyanatophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethy ester (XXIV). According to the procedure described byValli and Alper,¹⁹ a solution of the carbamate (XXXIV) (15.2 g, 40.6mmol) and Et₃ N (8.4 mL, 60 mmol) in anhydrous THF (300 mL) was refluxedunder N₂ for 5 min, and then allowed to cool for 10 min.Chlorocatecholborane (8.78 g, 57 mmol) was added, and the resultingmixture was refluxed under N₂ for 5 min. The solvent was then removed invacuo, and the residue was taken up in CH₂ Cl₂ (300 mL). The resultingsolution was washed with 1N aqueous HCl (150 mL), followed by 1N aqueousNaOH (150 mL). The organic extract was dried (Na₂ SO₄) and the solventwas removed in vacuo to furnish a cream solid (13.9 g, quantitativeyield): mp 170°-173° C.; ¹ H NMR (CDCl₃)δ 7.11 (m, 2H), 6.96 (s, 1H),6.86 (d, 1H, J=7.5 Hz), 5.74 (s, 1H), 4.97 (s, 1H), 3.65 (s, 6H), 2.34(s, 6H); ¹³ C NMR (CDCl₃) d 167.8, 149.2, 144.4, 133.0, 129.0, 125.3,124.0, 122.7, 103.5, 51.1, 39.3, 19.6; IR (KBr): 2272 cm⁻¹ ; Anal Calcdfor C₁₈ H₁₈ N₂ O₅ : C, 63.15; H, 5.30; N, 8.18. Found: C, 63.17; H,5.33; N, 7.98.

5. Intermediates of Formula (X)

Example 28:trans-1,2,3,4,4a,5,6,10b-Octahydro-9-methoxybenz[h]isoquinoline

a) 3,4-Dihydro-7-methoxy-1-naphthalenecarbonitrile. This compound wasprepared according to a method described by Basha.¹⁶ To a solution ofthe starting methoxytetralone (37.5 g, 213 mmol) in anhydrous THF (40mL) was added trimethylsilyl cyanide (25 g, 252 mmol), followed by LiCN(0.5M solution in DMF, 50 mL, 25 mmol). The resulting mixture wasstirred for 2 h, combined with Et₂ O (300 mL), and then rinsed with H₂ O(3×100 mL). The organic extract was rinsed with brine (50 ml), driedover Na₂ SO₄, and the solvent removed in vacuo to afford the cyanohydrinTMS ether as a light amber oil (62 g, 100% yield). Due to thewater-sensitive nature of this intermediate, further characterizationbeyond ¹ H NMR was not obtained, and the subsequent dehydration to thevinyl nitrile compound (XXIII) was immediately carried out.

The cyanohydrin TMS ether (62 g, 213 mmol) was placed in a three-neckedflask equipped with a Dean-Stark trap, and refluxed in dry toluene (200mL) containing conc. H₂ SO₄ (2.0 mL) for 30 min. The resulting solutionwas cooled, partitioned with 1N NaOH (100 mL), and rinsed with H₂ O (100mL). The organic extract was dried over Na₂ SO₄, and the solvent removedin vacuo to give (XXIII) as an amber oil (37.4 g, 95% yield): ¹ H NMR(CDCl₃)δ 7.04 (d, 1H, J=8.4 Hz), 6.98 (s, 1H), 6.88 (t, 1H, J=4.8 Hz),6.77 (d, 1H, J=8.4 Hz), 3.80 (s, 3H), 2.75 (t, 2H, J=8.7 Hz), 2.46 (m,2H); ¹³ C NMR (CDCl₃)δ 158.8, 144.5, 129.5, 128.8, 126.1, 117.1, 114,6,114.4, 110.2, 55.5, 25.2, 24.1. Anal. Calcd. for C₁₂ H₁₁ NO: C, 77.81;H, 5.99; N, 7.56. Found: C, 77.54; H, 5.86; N, 7.52.

b) 1-Cyano-7-methoxy-1,2,3,4-tetrahydro-2-naphthaleneacetic acid, ethylester (XXII). A solution of lithium diisopropylamide (LDA, 1.5M incyclohexane, 100 mL, 150 mmol) was combined with anhydrous THF (200 mL)at -78° C. under N₂ and stirred for 10 min. Anhydrous EtOAc (15 mL, 150mmol) was then added dropwise over 5 min, and the resulting solutionstirred for 30 min at -78° C. A solution of (XXIII) (25.0 g, 135 mmol)in anhydrous THF (75 mL) was added dropwise over 30 min, and stirringwas continued for an additional 10 min at -78° C. The reaction mixturewas allowed to warm to room temperature over 1 hr, and was subsequentlyquenched with saturated NH₄ Cl. Sufficient H₂ O was added to dissolveany solids, the aqueous extract discarded, and the organic extractrinsed with H₂ O (2×100 mL). The organic extract was reduced to drynessin vacuo, the residue taken up in CH₂ Cl₂, and the resulting solutiondried over Na₂ SO₄. The solvent was removed in vacuo, and distillationof the residue via a Kugelrohr apparatus (120°-210° C., 0.8 Torr)yielded (XXII) as a diastereomeric mixture. A yellow oil was obtained(31.9 g, 86% yield): ¹ H NMR (CDCl₃)δ 7.02 (d, 1H, J=8.4 Hz), 6.89, 6.74(s, 1H), 6.80 (m, 1H), 4.16 (m, 2H), 4.13, 3.87 (d, 1H, J=8.7 Hz), 3.78,3.77 (s, 3H), 2.61 (br m, 5H), 2.13, 1.57 (m, 1H), 1.85 (m, 1H), 1.27(m, 3H); Anal Calcd. for C₁₆ H₁₉ NO₃ •0.1 H₂ O: C, 69.85; H, 7.03; N,5.09. Found: C, 69.68; H, 6.91; N, 4.83.

c) trans-1,4,4a,5,6,10b-Hexahydro-9-methoxybenz[h]isoquinolin-3(2H)-one(XXI). A mixture of (XXII) (31.9 g, 117 mmol), MeOH (160 mL), 30%aqueous NH₃ (40 mL), and Raney nickel was shaken on a Parr apparatusunder H₂ (50 psi) overnight, resulting in the formation of a whiteprecipitate. The mixture was diluted with MeOH, and the resultingsuspension decanted from the catalyst. The solvent was removed in vacuofrom the suspension, and the residue dissolved in hot AcOH and filteredover Celite. The solvent was removed in vacuo from the filtrate, and theresidue triturated in H₂ O, filtered, and rinsed with H₂ O. Theresulting solid was recrystallized in EtOAc:AcOH 5:1 to afford the transisomer (XXIa) as a white solid (18.0 g, 67% yield): mp=255°-259° C.; ¹ HNMR (CD₃ CO₂ D) δ 11.65 (s, 1H), 7.04 (m, 1H), 6.76 (m, 2H), 4.03 (dd,1H, J=12.3, 5.1 Hz), 3.77 (s, 3H), 3.21 (t, 1H, J=11.7 Hz), 2.80 (m,3H), 2.68 (dd, 1H, J=18.0, 4.5 Hz), 2.26 (m, 1H), 1.85 (m, 2H), 1.46 (m,1H); ¹³ C NMR (CD₃ CO₂ D)δ 176.5, 158.8, 136.8, 131.0, 129.5, 112.9,112.2, 55.3, 47.1, 39.3, 38.0, 35.2, 29.4, 29.0. HRMS Calcd. for C₁₄ H₁₈NO₂ (M+H): 232.1338. Found: 232.1343. Subsequent crops obtained from themother liquor contained a mixture of (XXIa) and the cis isomer (XXIb).¹⁷

d) trans-1,2,3,4,4a,5,6,10b-Octahydro-9-methoxybenz[h]isoquinolinehydrochloride salt (X). A solution of (XXIa) (3.65 g, 15.8 mmol) inanhydrous THF (100 mL) containing BH₃ •Me₂ S (2M solution in THF, 17 mL,34 mmol) was refluxed overnight. The resulting mixture was then cooled,combined with MeOH (100 mL) and 1N HCl (100 mL), and stirred for 6 h.The organic solvents were then removed in vacuo. The resulting aqueoussuspension was made basic with 3N NaOH (50 mL) and partitioned with CH₂Cl₂ (3×100 mL). The organic extract was dried over Na₂ SO₄ and thesolvent removed in vacuo to give a white solid (3.5 g, quantitativeyield). A portion of this material was taken up in CH₂ Cl₂ and combinedwith a stoichiometric amount of 1N HCl in Et₂ O. The solvent was removedin vacuo to yield product as a white solid: mp=230°-232° C.; ¹ H NMR(DMSO-d₆)δ 9.51 (br s, 1H), 9.34 (br s, 1H), 7.00 (d, 1H, J=8.1 Hz),6.74 (m, 2H), 4.02 (d, 1H, J=9.6 Hz), 3.70 (s, 3H), 3.52 (br s, 2H),3.27 (d, 1H, J=12.3 Hz), 2.90 (m, 1H), 2.72 (m, 2H), 1.79 (m, 2H), 1.57(m, 2H), 1.38 (m, 1H); ¹³ C NMR (DMSO-d₆)δ 157.5, 136.0, 130.2, 128.3,112.5, 110.4, 55.2, 46.1, 43.0, 36.5, 29.0, 28.8, 27.9. Anal. Calcd. forC₁₄ H₁₉ NO•HCl•0.5 H₂ O: C, 63.99; H, 8.06; N, 5.33. Found: C, 64.08; H,7.86; N, 5.39.

B. Synthesis of Formula (I) Products

Example 29: General Procedure from Formula (III) Intermediates

The Formula (III) compound, e.g.1,4-Dihydro-4-[3-[[3-chloro-1-oxo-1-propyl]amino]phenyl]-1,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester (1.05 g, 2.53 mmol), compound (X) (3 mmol),micropulverized potassium carbonate (1.0 g, 7.2 mmol) and KI (1.0 g, 6.0mmol) are refluxed in CH₃ CN (50 mL) for 24 h. The solvent is removed invacuo and the residue is extracted with CH₂ Cl₂ /brine. The CH₂ Cl₂layer, dried over Na₂ SO₄, and the solvent is removed in vacuo and theconcentrate chromatographed over silica gel (1:4 to 1:0 EtOAc:hexanegradient) to give an anilide product as a pale yellow foam. The baseproduct is then converted to an acceptable salt, purified andcharacterized.

Example 30: General Procedure from Formula (II) Intermediates

To a solution of the requisite aniline (IV) (6 mmol) under N₂ in 30 mLof CH₂ Cl₂, was added 7 mmol of 3-chloropropyl isocyanate. The reactionwas then stirred at room temperature or at reflux until judged completeby TLC analysis (2-24 h). The solution was washed with H₂ O and brineand then dried over MgSO₄. After filtration, the volatiles were removedin vacuo and the residue was taken up in 35 mL of MeCN. To this solutionwas added the appropriate Formula (X) nitrogen heterocyclic compound (10mmol), micropulverized K₂ CO₃ (7 mmol), and a catalytic amount of Nal(10 mg). The resulting suspension was allowed to reflux overnight underN₂ and then poured into 100 mL of H₂ O. After extraction with CH₂ Cl₂,the combined organic fractions were washed with H₂ O and brine, anddried over MgSO₄. The suspension was filtered and the filtrateconcentrated in vacuo to furnish the crude products of Formula (I).These were then purified by flash chromatography (SiO₂ : ammoniatedEtOAc/MeOH) and a salt generally prepared from the free base.

There were, in general, two variations on this procedure.

Method A. The chloroalkyl dihydropyridines (II) (2.2 mmol) werealkylated as a neat melt at 134° C. with the desired Formula (X)compounds (2.2 mmol). The reaction was monitored by TLC and typicallywere completed in 15 minutes to an hour. The crude mixtures werepurified initially by flash chromatography (SiO₂ :EtOAc/MeOH) followedby preparative plates (0.5 mm SiO₂ plates) eluted with MeOH or 10%MeOH/CH₂ /Cl₂.

Method B. The chloroalkylurea dihydropyridines (II) (2.2 mmol) werealkylated with the corresponding Formula (X) compounds (2.0-2.2 mmol)using potassium carbonate (3.5 mmol) and sodium iodide (1.0-3.5 mmol).The reactions were refluxed 14 hrs and after cooling filtered through aplug of celite. The crude materials were then concentrated down in vacuoto a form which was purified by flash chromatography (CH₂ Cl₂ /MeOH) andpreparative chromatography.

Example 31: General Procedure from Formula (XXXIV) Intermediate

A solution of the appropriate isocyanato derivative of Formula (XXXIV)(about 30 mmole) and aminoalkylpiperidine intermediate of Formula (XX)(about 40 mmole) in methylene chloride (500 mL) were stirred for severalhrs. The reaction mixture was flash chromatographed in silica geleluting with CH₂ Cl₂ -5 to 10% MeOH. Removal of solvent in vacuo affordsthe crude base of the Formula (I) compound which is then usuallyconverted into salt form and purified.

Example 32:1,4-Dihydro-4-[3-[[[[3-[spiro(2,3-dihydroindene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester, fumarate salt

This compound was isolated as a light yellow solid in 29% yield (methodC): mp 200°-205° C.; ¹ H NMR (DMSO-d₆)δ 8.88 (s, 1H), 8.71 (s, 1H), 7.28(m, 6H), 7.02 (m, 2H), 6.82 (d, 1H, J=6 Hz), 6.65 (d, 1H, J=6 Hz), 6.57(s, 2H), 6.53 (br s, 1H), 4.84 (s, 1H), 3.54 (s, 6H), 3.27 (m, 2H), 3.16(br s, 2H), 2.81 (m, 4H), 2.24 (s, 8H), 1.79 (m, 2H), 1.27 (d, 2H, J=15Hz); ¹³ C NMR (DMSO-d₆)δ 167.5, 167.2, 155.5, 151.3, 148.1, 145.6,142.5, 141.3, 140.4, 134.7, 129.9, 128.2, 127.0, 125.4, 121.6, 121.3,119.7, 116.5, 115.5, 101.4, 54.7, 50.9, 50.7, 50.7, 36.9, 35.7, 31.8,25.9, 18,6, 18.2; Anal. Calcd. for C₃₄ H₄₀ N₄ O₅ •1.0 C₄ H₄ O₄ •1.9 H₂O: C, 62.10; H, 6.56; N, 7.62. Found: C, 61.81; H, 6.39; N, 7.38; HRMSCalcd. for C₃₄ H₄₁ N₄ O₅ (M+H): 585.3077. Found: 585.3056.

Example 33:1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester, fumarate salt

This compound was isolated as a light yellow solid in 25% yield (methodC): mp 200°-203° C.; ¹ H NMR (CDCl₃)δ 8.58 (br s, 1H), 8.04 (br.s., 1H),7.54 (d, 1H, J=6 Hz), 7.26 (s, 1H), 7.02 (m, 7H), 4.93 (s, 1H), 3.56 (s,6H), 3.41 (br s, 2H), 3.26 (br s, 2H), 3.01 (br s, 2H), 2.87 (m, 2H),2.72 (br s, 2H), 2.26 (s, 8H), 1.94 (m, 4H), 1.64 (m, 2H); HRMS Calcd.for C₃₄ H₄₃ N₄ O₅ (M+H): 587.3234 Found: 587.3212.

Example 34:1,4-Dihydro-4-[3-[[[[3-(1,2,3,4-tetrahydroisoquinoline)propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester, fumarate salt

This compound was isolated as a light yellow solid in 42% yield (methodC): mp 140°-143° C.; ¹ H NMR (DMSO-d₆)δ 8.86 (s, 1H), 8.53 (s, 1H),7.26-7.23 (m, 1H), 7.15-6.99 (m, 6H), 6.66-6.64 (m, 1H), 6.57 (s, 4H),6.31 (s, 1H), 4.84 (s, 1H), 3.77 (s, 2H), 3.54 (s, 6H), 3.14-3.12 (m,2H), 2.87 (s, 4H), 2.66 (t, 2H, J=7 Hz), 2.24 (s, 6H), 1.75-1.71 (m,2H); ¹³ C NMR (DMSO-d₆)δ 167.5, 166.8, 155.4, 148.1, 145.6, 140.4,134.4, 133.5, 133.2, 128.4, 128.2, 126.5, 126.4, 125.8, 119.7, 116.5,115.5, 101.4, 54.6, 50.6, 49.9, 37.1, 27.7, 26.6, 18.2; Anal. Calcd. forC₃₀ H₃₆ N₄ O₅ •1.0 C₄ H₄ O₄ •0.6 H₂ O: C, 61.92; H, 6.30; N, 8.50.Found: C, 61.68, H, 6.30; N, 8.44.

Example 35:1,4-Dihydro-4-[3-[[[[3-[2-(trans-1,2,3,4,4a,5,6,10b-octahydrobenz[h]isoquinolinyl)]propyl]amino]carbonyl]amino]phenyl]-2,6-pyridinedicarboxylicacid, dimethyl ester, hydrochloride salt

This compound was isolated as an amber solid in 38% (method B): mp95°-100° C.; ¹ H NMR (DMSO-d₆)δ 10.47 (br s, 1H), 8.95 (s, 1H), 8.76 (s,1H), 7.29 (d, 1H, J=8.4 Hz), 7.09 (s, 1H), 7.00 (m, 2H), 6.84 (s, 1H),6.75 (d, 1H, J=8.4 Hz), 6.65 (d, 1H, J=7.8 Hz), 6.51 (br s, 1H), 4.83(s, 1H), 4.24 (d, 1H, J=9.3 Hz), 3.78 (s, 3H), 3.54 (s, 6H), 3.50 (m,3H), 3.17 (m, 2H), 2.87 (m, 3H), 2.74 (m, 2H), 2.25 (s, 6H), 1.81 (m,5H), 1.44 (m, 2H); ¹³ C NMR (DMSO-d₆)δ 167.5, 157.6, 155.6, 148.1,145.7, 140.3, 135.7, 130.3, 128.3, 119.8, 116.5, 115.5, 112.5, 110.5,101.3, 55.3, 54.9, 54.5, 51.3, 50.7, 39.4, 38.4, 36.5, 36.3, 29.3, 28.4,27.9, 24.5, 18.2. Anal. Calcd. for C₃₅ H₄₄ N₄ O₆ •HCl•2 H₂ O: C, 60.99;H, 7.17; N, 8.13. Found: C, 61.37; H, 6.86; N, 7.71. ##STR11##

References and Notes

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We claim:
 1. A compound of Formula (I) and its pharmaceuticallyacceptable ##STR12## acid addition salts or hydrates thereof, wherein R¹is lower alkyl;R² and R³ are independently selected from cyano and loweralkyl; R⁴ is selected from --CO₂ R¹, cyano and ##STR13## R⁵ is selectedfrom hydrogen, halogen, hydroxy, lower alkyl, lower alkenyloxy, andlower alkoxy; B is --NH-- or a covalent bond; n is an integer selectedfrom 2 to 5; and Z is selected from the group consisting of ##STR14##with the solid and dotted lines representing either a single or doublecovalent bond.
 2. A compound of claim 1 wherein B is --NH--.
 3. Acompound of claim 1 wherein B is a covalent bond.
 4. A compound of claim1 wherein Z is ##STR15##
 5. A compound of claim 4 selected from1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester;1,4-Dihydro-4-[3-[[[[3-[spiro(2,3-dihydroindene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester.
 6. A method of promoting weight lossand treating eating disorders in a mammal which comprises administeringto a mammalian host an anorexiant effective dose of a compound claimedin claim
 1. 7. A pharmaceutical composition for use in promoting weightloss and treating eating disorders. The composition comprises ananorexiant effective amount of a compound claimed in claim 1 incombination with a pharmaceutically acceptable carrier.
 8. A method ofpromoting weight loss and treating eating disorders in a mammal whichcomprises administering to a mammalian host an anorexiant effective doseof a compound claimed in claim
 5. 9. A pharmaceutical composition foruse in promoting weight loss and treating eating disorders. Thecomposition comprises an anorexiant effective amount of a compoundclaimed in claim 5 in combination with a pharmaceutically acceptablecarrier.